DNP-MRSI for the Detection of Latent, Treatment-Resistant Cellular Domains in HCC

评估实体瘤对治疗的反应的既定指南是基于常规成像 指标，如肿瘤大小和血管分布，旨在促进对 全身施用的化疗剂靶向灌注良好的微环境中的增殖细胞。 一种新出现的肿瘤复发的影像学表型表明，完全放射学反应可能是 随后是可变的潜伏期，在灌注不良的微环境中没有可察觉的增长。这 成像表型突出了癌细胞适应其生长程序的能力， 微环境和影响肿瘤休眠，并强调了发展功能成像的重要性 范例，使他们的检测。 经动脉化疗栓塞术（TACE）治疗肝细胞癌（HCC）提供了一种新的治疗方法， 令人信服的临床相关性，这种成像缺陷。TACE利用HCC的血管生物学， 肿瘤的营养，导致坏死;然而，只有44%的大型治疗病变表现出广泛的 坏死的病理，强调肝癌细胞的适应性反应，营养剥夺。这种自适应 反应反映在组织病理学上坏死区域附近存在存活的肿瘤细胞， 并且与在随访成像中经常观察到的潜伏期后的快速复发一致。在 在临床前研究中，我们证明：1）TACE诱导缺血后存活的HCC细胞被重编程， 将葡萄糖碳分流到乳酸盐，为检测这些细胞提供独特的特征; 2）基于 这种重编程，动态核磁极化磁-13碳-磁共振光谱 高碘化（HP）1- 13 C-丙酮酸盐的成像（DNP-13 C-MRSI）能够更灵敏地检测HCC 与标准护理（SOC）MRI相比，用于TACE反应评估的细胞;以及3）检测 TACE难治性细胞结构域将通过识别分子依赖性为靶向治疗提供信息。 我们假设HP 1- 13 C-丙酮酸的DNP-13 C-MRSI提供了一种独特的技术，通过该技术， 利用TACE存活的HCC细胞中的代谢重编程，并实现功能性分子成像 对患者进行有效的治疗反应评估。为了验证这一假设，拟议的项目将继续 两个主要目的：（1）验证体内肝动脉相DNP-13 C-MRSI的优化脉冲序列 使用临床成像系统检测HCC中HP 1- 13 C-丙酮酸。(2a)确定DNP-13 C-MRSI的灵敏度 HP 1- 13 C-丙酮酸摄取和代谢用于确定完全缓解患者的局部复发 TACE，如通过当前SOC成像反应标准所测量的;以及（2b）确定DNP的准确性- HP 1- 13 C-丙酮酸至乳酸和丙氨酸的13 C-MRSI用于检测靶向代谢应激 TACE后HCC细胞的反应。实现拟议目标有可能改变 肝癌是一种毁灭性的疾病，

Established guidelines for assessing response of solid tumors to therapy are based on conventional imaging indices, such as tumor size and vascularity, and were intended to facilitate a uniform assessment of response to systemically administered chemotherapeutics that target proliferating cells in a well-perfused microenvironment. An emerging imaging phenotype of tumor recurrence indicates that a complete radiographic response may be followed by variable periods of latency without perceptible growth in poorly perfused microenvironments. This imaging phenotype highlights the capability of cancer cells to adapt their growth program to their microenvironment and effect tumor dormancy and underscores the importance of developing functional imaging paradigms to enable their detection. Transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) provides a compelling clinical correlate to this imaging deficiency. TACE exploits the vascular biology of HCC to deprive tumors of nutrients, leading to necrosis; however, only 44% of large treated lesions demonstrate extensive necrosis on pathology, underscoring the adaptive response of HCC cells to nutrient deprivation. This adaptive response is reflected by the presence of viable tumor cells adjacent to regions of necrosis on histopathology, and is consistent with the rapid recurrence following a period of latency often observed on follow-up imaging. In preclinical studies, we demonstrated that: 1) HCC cells surviving TACE-induced ischemia are reprogrammed to shunt glucose carbons toward lactate, providing a unique signature for the detection of these cells; 2) based on this reprogramming, Dynamic Nuclear Polarization Magnetic-13Carbon-Magnetic Resonance Spectroscopic Imaging (DNP-13C-MRSI)of hyperoplarized (HP) 1-13C-pyruvate enables the more sensitive detection of HCC cells for response assessment to TACE as compared to standard-of-care (SOC) MRI; and 3) the detection of TACE-refractory cellular domains will inform targeted therapy by identifying molecular dependencies. We hypothesize that DNP-13C-MRSI of HP 1-13C-pyruvate provides a unique technology through which to leverage the metabolic reprogramming in HCC cells surviving TACE and enable functional molecular imaging for effective treatment response assessment in patients. To test this hypothesis the proposed project will pursue two primary aims: (1) to validate an optimized pulse sequence for in vivo hepatic arterial phase DNP-13C-MRSI of HP 1-13C-pyruvate in HCC using clinical imaging systems.; (2a) to determine the sensitivity of DNP-13C-MRSI of HP 1-13C-pyruvate uptake and metabolism for identifying local recurrence in patients with a complete response to TACE, as measured by current SOC imaging response criteria; and (2b) to determine the accuracy of DNP- 13C-MRSI of HP 1-13C-pyruvate to lactate and alanine for the detection of the targetable metabolic stress response in HCC cells following TACE. The achievement of the proposed aims holds the potential to transform the imaging and treatment of patients with HCC, a devastating disease.